rs1804495

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000354.6(SERPINA7):c.909G>T(p.Leu303Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,204,797 control chromosomes in the GnomAD database, including 7,019 homozygotes. There are 52,359 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 616 hom., 3967 hem., cov: 23)

Exomes 𝑓: 0.13 ( 6403 hom. 48392 hem. )

Consequence

SERPINA7
NM_000354.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:2B:4

Conservation

PhyloP100: -1.06

Variant links:

Genes affected

SERPINA7 (HGNC:11583): (serpin family A member 7) There are three proteins including thyroxine-binding globulin (TBG), transthyretin and albumin responsible for carrying the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in the bloodstream. This gene encodes the major thyroid hormone transport protein, TBG, in serum. It belongs to the serpin family in genomics, but the protein has no inhibitory function like many other members of the serpin family. Mutations in this gene result in TGB deficiency, which has been classified as partial deficiency, complete deficiency, and excess, based on the level of serum TBG. Alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of these variants has not been determined.[provided by RefSeq, Jun 2012]

SERPINA7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003224343).

BP6

Variant X-106034370-C-A is Benign according to our data. Variant chrX-106034370-C-A is described in ClinVar as [Benign]. Clinvar id is 9785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-106034370-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SERPINA7	NM_000354.6 linkuse as main transcript	c.909G>T	p.Leu303Phe	missense_variant	4/5	ENST00000372563.2
SERPINA7	XM_006724683.3 linkuse as main transcript	c.909G>T	p.Leu303Phe	missense_variant	4/5
SERPINA7	XM_005262180.5 linkuse as main transcript	c.909G>T	p.Leu303Phe	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SERPINA7	ENST00000372563.2 linkuse as main transcript	c.909G>T	p.Leu303Phe	missense_variant	4/5	5	NM_000354.6	P1
SERPINA7	ENST00000327674.8 linkuse as main transcript	c.909G>T	p.Leu303Phe	missense_variant	3/4	1		P1
SERPINA7	ENST00000487487.1 linkuse as main transcript	n.182G>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.122

AC:

13603

AN:

111367

Hom.:

618

Cov.:

AF XY:

0.118

AC XY:

3960

AN XY:

33625

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.146

Gnomad EAS

AF:

0.236

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.0788

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.112

GnomAD3 exomes

AF:

0.142

AC:

25859

AN:

182266

Hom.:

1319

AF XY:

0.150

AC XY:

10025

AN XY:

67052

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.154

Gnomad EAS exome

AF:

0.248

Gnomad SAS exome

AF:

0.289

Gnomad FIN exome

AF:

0.0852

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.122

GnomAD4 exome

AF:

0.128

AC:

140495

AN:

1093377

Hom.:

6403

Cov.:

AF XY:

0.135

AC XY:

48392

AN XY:

359617

show subpopulations

Gnomad4 AFR exome

AF:

0.115

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.151

Gnomad4 EAS exome

AF:

0.196

Gnomad4 SAS exome

AF:

0.287

Gnomad4 FIN exome

AF:

0.0907

Gnomad4 NFE exome

AF:

0.118

Gnomad4 OTH exome

AF:

0.140

GnomAD4 genome

AF:

0.122

AC:

13601

AN:

111420

Hom.:

616

Cov.:

AF XY:

0.118

AC XY:

3967

AN XY:

33688

show subpopulations

Gnomad4 AFR

AF:

0.118

Gnomad4 AMR

AF:

0.103

Gnomad4 ASJ

AF:

0.146

Gnomad4 EAS

AF:

0.236

Gnomad4 SAS

AF:

0.294

Gnomad4 FIN

AF:

0.0788

Gnomad4 NFE

AF:

0.114

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.120

Hom.:

10183

Bravo

AF:

0.124

TwinsUK

AF:

0.117

AC:

435

ALSPAC

AF:

0.118

AC:

341

ESP6500AA

AF:

0.123

AC:

472

ESP6500EA

AF:

0.112

AC:

751

ExAC

AF:

0.145

AC:

17641

EpiCase

AF:

0.115

EpiControl

AF:

0.121

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Thyroxine-binding globulin, variant P

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1992

- -

Thyroxine-binding globulin quantitative trait locus

Pathogenic:1

Likely risk allele, no assertion criteria provided

clinical testing

Department of Endocrinology, The Fourth Affiliated Hospital of Guangzhou Medical University

- -

SERPINA7-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 25, 2021

This variant is associated with the following publications: (PMID: 33554479, 2155256, 1515456, 25333069) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T

FATHMM_MKL

Benign

0.16

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.4

M;M

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

0.98

D;D

Vest4

0.17

MutPred

0.30

Gain of methylation at K298 (P = 0.093);Gain of methylation at K298 (P = 0.093);

MPC

0.15

ClinPred

0.068

GERP RS

2.5

Varity_R

0.82

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over